This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This goal of this project is to identify host cell-pathways essential for flavivirus replication or for anti-flavivirus immune responses. We will identify these pathways by using a systematic chemical genomics approach to identify host cell kinase networks that modulate flavivirus replication. By cell-based screening of kinase-directed small molecule libraries for inhibitors of Dengue-virus (DENV) replication, we expect to identify kinase inhibitors that inhibit different steps of the DENV life cycle. In secondary screens we will select compounds with a high selectivity index, broad cell type specificity and activity against other flaviviruses (WNV, JEV, YFV). The kinases targeted by a given compound will be identified by combining computational, functional genomics and biochemical approaches. The importance of cellular pathways thus identified for flavivirus replication will be evaluated by gene knockdown of key components of a given host cell pathway. Selected compounds will be tested in vivo using a West Nile Virus animal model.